Patent NZ-333824-A (NZ)
Title: Thiol sulfone metalloprotease inhibitors
Inventor: FRESKOS JOHN N
IPC: A61K31/22
Filed: 1997-07-22
Abstract: Matrix metalloproteinase-13 (MMP-13), also known as collagenase III, can be destructive to connective tissue if present in abnormal concentrations.  The thiol sulfonamide compounds of the formulae above are examples of inhibitors of MMP-13, and can be used to treat pathological conditions caused by the proteinase.  x and y are independently zero, 1 or 2; W is oxygen or sulfur; a starred R* group, y* or x* is the same or different from an unstarred R, y or x; R1 is preferably a substituted aryl or heteroaryl ring that is substituted in the para-position (4 position) by one or more of the following substituents: C1-6 alkyl, C1-6 alkoxy, arylcarboxamido, heteroarylcarboxamido, arylazo, heteroarylazo, aryloxy, heteroaryloxy, aryl, heteroaryl, aralkoxy, heteroaralkoxy, C1-6 alkylthio, arylthio, heteroarylthio in which each ring-containing substituent itself contains a single ring; R2 and R3 are preferably selected from the group consisting of hydrido, C1-6 alkyl, aralkyl, heteroaralkyl, cycloalkylalkyl having 4-8 carbons in the ring and 1-3 carbons in the alkyl chain, heterocycloalkylalkyl in which 4-8 atoms are in the ring, one or two of which atoms can be N, O or S, and in which the alkyl chain contains 1-3 carbons, C1-5 alkyl substituted by hydroxycarbonyl, amino, monosubstituted amino and di-substituted amino, wherein the substituents on nitrogen are chosen from C14q alkyl, aralkyl, C5-8 cycloalkyl and C1-6 alkanoyl groups, or wherein the two substituents and the nitrogen to which they are attached when taken together form a 5- to 8-membered heterocyclo or heteroaryl ring. R4 and R5 are preferably selected from the group consisting of hydrido, amino, alkanoylamino, arylcarbonylamino, heterocarbonylamino, hydroxycarbonyl, aminocarbonyl, C1-6 alkyl, aralkyl aryl heteroaryl, cycloalkyl, heteroaralkyl, or alkylcycloalkyl. R6 and R7 are preferably selected from the group consisting of hydrogen (hydrido) hydroxy, cycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, C1-6 alkyl, carboxyl, C1-6 alkoxy carbonyl,  amino C1-6 alkanoyl, or a carboxamide group where the amido nitrogen is: (i) unsubstituted; or (ii) substituted with a C1-4 alkyl substituted by amino, mono-substituted amino or di-substituted amino, wherein the substituent on the amino nitrogen is selected from the group consisting of C1-6 alkyl, C5-8 cycloalkyl and C1-6 alkanoyl groups, or wherein two amino nitrogen substitutents and the nitrogen to which they are bonded together form a 5- to 8-membered heterocyclic or heteroaryl ring containing 0 or 1 additional hetero atoms that are N, O or S; or (iii) the amine of an amino acid;  R8 and R9 are preferably selected from the group consisting of hydrido, hydroxycarbonyl, C1-6 alkyl, aryl, heteroaryl, aralkyl or heteroaralkyl; R10 is preferably selected from the group consisting of alkyl, aryl, alkoxy, heteroaryl, cycloalkyl, aryloxy, aminoalkyl, and N-monosubstituted aminoalkyl or N,N-disubstituted aminoalkyl, wherein the substituents on the nitrogen is selected from the group consisting of alkyl, aralkyl, cycloalkyl, and alkanoyl, or wherein the nitrogen and two substituents attached form a 5 to 8 membered heterocyclo or heteroaryl ring.